Submission Details

Autosomal dominant STAT1 gain of function mutations were first reported to be associated with autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome in 2011 (PMIDs: 21714643 and 21727188). Among the reported STAT1-GOF patients, more than 100 different missense variants were detected; most were in the coiled-coil domain and DNA binding domain. R274Q, A267V, T385M, and R274W are hotspot mutations identified in nearly 40% of all patients with STAT1-GOF (PMIDs: 27114460, 32852681 and 33777053). STAT1 GOF mutations underlie AD Chronic Mucocutaneous Candidiasis (CMC), as well as a wide range of other clinical features, including a variety of infectious and autoimmune diseases, cerebral aneurysms and cancers (PMID: 27114460). Thyroid dysfunction and autoimmune diabetes are among the most frequent autoimmune manifestations reported, at 22% and 4% respectively. 10 missense variants are included in this curation to reach the maximum score for genetic evidence (PMIDs: 21727188, 23541320, 23534974, 22730530, 28139313). Counting disease segregation in 2 families provided a LOD score of 3 and added 1 point to the genetic evidence (PMID: 21727188). More case-level evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached.

The reported STAT1-GOF mutations are demonstrated to result in gain of STAT1 phosphorylation and gain of function for GAF-dependent cellular responses (PMID: 21727188). Also, Impaired development and function of IL-17 and IL-22- producing T cells ex vivo are detected in patients with AD CMCD having STAT1 GOF mutations. IFN-γ induced prolonged STAT1 phosphorylation in gain of function mutants and significant diminution of IL-17+FOXP3−CD4+ cells (Th17) were also shown in patients with autoimmune manifestations. Consistent with the phenotype of patients with GOF-STAT1 mutations, GOF-Stat1 mice had increased STAT1 protein levels, enhanced pSTAT1 upon IFN-γ stimulation and defective IL-17 production after C. albicans inoculation (PMID: 31867619). In a specific pathogen-free model, Stat1T385M/+ mice developed sex-biased autoimmunity and exhibited pronounced dysregulation of basal and cytokine-stimulated Stat1 activation (PMID: 37275873).

Janus kinase inhibitor therapy ruxolitinib was shown to decrease STAT1 phosphorylation in response to stimulation with IFN-β and IFN-γ, reverse dysregulated T helper cell responses and lead to resolution of the chronic mucocutaneous candidiasis and autoimmunity caused by STAT1- gain of function mutations (PMID: 28139313). In a multicenter retrospective study (Fischer et al., 2024 PMID: 37935260), JAK inhibitor treatment resulted in partial or complete remission of clinical symptoms in most investigated patients with STAT1-GOF.

In summary, there is definitive evidence supporting the relationship between STAT1 and autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld overtime.

Diabetes Addendum (approved by Monogenic Diabetes GCEP 10/23/2024):

Autosomal dominant STAT1 GOF variants were first implicated in diabetes in 2013. Three patients with polyendocrinopathy, enteropathy, dermatitis, recurrent mucosal and fungal infections, and autoimmune diabetes were found to have STAT1 GOF variants. The patients were diagnosed with autoimmune diabetes (two GAD+) between 11 months (presenting with ketoacidosis) and 5 years of age (PMID: 23534974). A subsequent international case series of 274 patients from 167 kindreds with STAT1 variants revealed 11 (4%) patients with autoimmune diabetes. Within this STAT1 cohort, aneurysms were more common (27% vs. 5%) in patients with autoimmune diabetes (PMID: 27114460). While diabetes has only been seen in a minority of patients, the prevalence is increased over the general population and cases reported have a young age of onset. Therefore, STAT1 is appropriate to be included on clinical panels for neonatal diabetes. Individuals found to have a STAT1 variant causative of diabetes should be monitored for other autoimmune enteropathy and endocrinopathy and susceptibility to chronic infections, and those with non-diabetes presentations should undergo glycemic screening.